Lay Description: The testing of drugs that may slow the progression of osteoarthritis (OA) can be helped by the use of subjects whose OA is likely to worsen rapidly. This research will evaluate the ability of several molecular markers of cartilage deterioration and repair to identify subjects with progressive knee OA. Since 1996, investigators at Indiana University have conducted several NIH-funded investigations into structural progression of knee OA. These studies employed a fluoroscopically assisted radiography that permitted an unprecedented degree of standardization of the radioanatomic position of the knee in serial examinations over 30 months. These studies include the first successful demonstration of structure modifying drug in knee OA in the United States and re-evaluation of standard risk factors for incident and progressive radiographic changes of knee OA. Analyses of the clinical and radiographic data from these studies have yielded new information that has advanced the study of the progression of knee OA. Samples of plasma and urine were obtained serially from the subjects in these studies and have been used in a series of pilot studies to evaluate the capacity of an extensive array of molecular markers of disease activity in OA to distinguish subjects with radiographically and/or symptomatically progressive knee OA from those with stable disease. Based on the results of these pilot studies, the Specific Aims of the present application are designed to: (1) evaluate the extent to which baseline concentrations of selected molecular markers (i.e., plasma stromelysin (MMP-3), urinary C-terminal crosslinking telopeptide of Type II collagen (CTX-II) and Type II collagen turnover (C2C:CPII) predict the progression of knee OA over intervals of 16 and 30 months; (2) to evaluate the extent to which serial concentrations of MMP-3 and aggrecan chondroitin sulfate 846 epitope (CS846, a marker of proteoglycan synthesis) reflect concurrent progression of knee OA; and (3) To evaluate the suitability of MMP-3 and CS846 to serve as surrogate outcomes in a positive randomized, placebo-controlled clinical trial of structure modification in knee OA. The quality of radiographic data from these studies, and resulting sensitivity to disease progression, will enable new investigations into the utility of molecular markers OA that will advance our knowledge of pathophysiology and structure modification in knee OA with greater precision than has been historically possible with conventional radiographic methods. [unreadable] [unreadable] [unreadable]